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Acta Biochimica et Biophysica Sinica 2009 41(1):30-41; doi:10.1093/abbs/gmn004
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© The Author 2009. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

The optional long 5'-untranslated region of human ACAT1 mRNAs impairs the production of ACAT1 protein by promoting its mRNA decay

Xiaonan Zhao1,{dagger}, Jia Chen1,{dagger}, Lei Lei1, Guangjing Hu1, Ying Xiong1, Jiajia Xu1, Qin Li1, Xinying Yang1, Catherine C.Y. Chang2, Baoliang Song1, Tayuan Chang2 and Boliang Li1,*

1 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2 Department of Biochemistry, Dartmouth Medical School, Hannover, NH 03756, USA

* Corresponding author: Tel, 86-21-5492-1278; Fax, 86-21-5492-1279; E-mail, blli{at}sibs.ac.cn


  Abstract

We have previously reported that human ACAT1 mRNAs produce the 50 kDa protein using the AUG1397–1399 initiation codon, and also a minor 56 kDa isoform using the upstream in-frame GGC1274–1276 initiation codon. The GGC1274–1276 codon is located at the optional long 5'-untranslated region (5'-UTR, nt 1–1396) of the mRNAs. The DNA sequences corresponding to this 5'-UTR are located in two different chromosomes, 7 and 1. In the current work, we report that the optional long 5'-UTR significantly impairs the production of human ACAT1 protein initiated from the AUG1397–1399 codon, mainly by promoting its mRNA decay. The western blot analyses indicated that the optional long 5'-UTR potently impaired the production of different proteins initiated from the AUG1397–1399 codon, meaning that this impairing effect was not influenced by the 3'-UTR or the coding sequence of ACAT1 mRNA. The results of reverse transcription-quantitative polymerase chain reaction demonstrated that this 5'-UTR dramatically reduced the contents of its linked mRNAs. Analyses of the protein to mRNA ratios showed that this 5'-UTR mainly decreased its mRNA stability rather than altering its translational efficiency. We next performed the plasmid transfection experiments and used actinomycin D to inhibit transcription. The results showed that this 5'-UTR promoted its mRNA decay. Additional transfection and nucleofection experiments using RNAs prepared in vitro illustrated that, in both the cytoplasm and the nucleus of cells, the optional long 5'-UTR-linked mRNAs decayed faster than those without the link. Overall, our study brings new insight to the regulation of the human ACAT1 gene expression at the post-transcription level.

Keywords    human ACAT1 mRNA; long 5'-UTR; mRNA stability; mRNA decay; ACAT1 protein production

Received: July 13, 2008; Accepted: August 20, 2008

{dagger} These authors contributed equally to this manuscript


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